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Molecular and Cellular Biology, April 2007, p. 2601-2614, Vol. 27, No. 7
0270-7306/07/$08.00+0     doi:10.1128/MCB.01740-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Inverted DNA Repeats Channel Repair of Distant Double-Strand Breaks into Chromatid Fusions and Chromosomal Rearrangements{triangledown} ,{dagger}

Kelly VanHulle,1 Francene J. Lemoine,2 Vidhya Narayanan,3 Brandon Downing,1 Krista Hull,1 Christy McCullough,1 Melissa Bellinger,1 Kirill Lobachev,3 Thomas D. Petes,2 and Anna Malkova1*

Department of Biology, School of Science, IUPUI, Indianapolis, Indiana 46202,1 Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, North Carolina 27710,2 School of Biology, Georgia Institute of Technology, Atlanta, Georgia 303323

Received 14 September 2006/ Returned for modification 14 October 2006/ Accepted 12 January 2007

Inverted DNA repeats are known to cause genomic instabilities. Here we demonstrate that double-strand DNA breaks (DSBs) introduced a large distance from inverted repeats in the yeast (Saccharomyces cerevisiae) chromosome lead to a burst of genomic instability. Inverted repeats located as far as 21 kb from each other caused chromosome rearrangements in response to a single DSB. We demonstrate that the DSB initiates a pairing interaction between inverted repeats, resulting in the formation of large dicentric inverted dimers. Furthermore, we observed that propagation of cells containing inverted dimers led to gross chromosomal rearrangements, including translocations, truncations, and amplifications. Finally, our data suggest that break-induced replication is responsible for the formation of translocations resulting from anaphase breakage of inverted dimers. We propose a model explaining the formation of inverted dicentric dimers by intermolecular single-strand annealing (SSA) between inverted DNA repeats. According to this model, anaphase breakage of inverted dicentric dimers leads to gross chromosomal rearrangements (GCR). This "SSA-GCR" pathway is likely to be important in the repair of isochromatid breaks resulting from collapsed replication forks, certain types of radiation, or telomere aberrations that mimic isochromatid breaks.

* Corresponding author. Mailing address: Biology Department, IUPUI, 723 West Michigan Street, Indianapolis, IN 46202-5132. Phone: (317) 278-5717. Fax: (317) 274-2946. E-mail: amalkova{at}iupui.edu.

{triangledown} Published ahead of print on 22 January 2007.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, April 2007, p. 2601-2614, Vol. 27, No. 7
0270-7306/07/$08.00+0     doi:10.1128/MCB.01740-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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